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Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

A Randomized Double-Blind Phase III Study of Ibrutinib During and Following Autologous Stem Cell Transplantation Versus Placebo in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma of the Activated B-Cell Subtype

Status
Active, not recruiting
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02443077
Enrollment
94
Registered
2015-05-13
Start date
2016-10-12
Completion date
2026-12-23
Last updated
2026-04-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Recurrent Diffuse Large B-Cell Lymphoma Activated B-Cell Type, Refractory Diffuse Large B-Cell Lymphoma Activated B-Cell Type

Brief summary

This randomized phase III trial studies ibrutinib to see how well it works compared to placebo when given before and after stem cell transplant in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Before transplant, stem cells are taken from patients and stored. Patients then receive high doses of chemotherapy to kill cancer cells and make room for healthy cells. After treatment, the stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Ibrutinib is a drug that may stop the growth of cancer cells by blocking a protein that is needed for cell growth. It is not yet known whether adding ibrutinib to chemotherapy before and after stem cell transplant may help the transplant work better in patients with relapsed or refractory diffuse large B-cell lymphoma.

Detailed description

PRIMARY OBJECTIVE: I. To evaluate the ability of ibrutinib to improve 24-month progression free survival (PFS) compared to placebo in patients with non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) as determined by immunohistochemistry (IHC). SECONDARY OBJECTIVES: I. To evaluate the ability of ibrutinib to improve overall survival (OS) compared to placebo. II. To evaluate the ability of ibrutinib to improve progression free survival (PFS) compared to placebo. III. To evaluate the ability of ibrutinib to improve post-transplant response rates compared to placebo. IV. To evaluate time to hematopoietic recovery in the two arms. V. To evaluate the safety and tolerability of ibrutinib compared to placebo. VI. To evaluate the incidence of secondary malignancies in the two arms. VII. To evaluate immune reconstitution in the two arms. CORRELATIVE SCIENCE OBJECTIVES: I. To assess whether pre-autologous hematopoietic stem cell transplantation (AutoHCT) positive fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) is associated with inferior 24-month PFS as well as PFS and OS. II. To assess whether pre-AutoHCT FDG-PET results are differentially associated with 24-month PFS, PFS and OS in the ibrutinib versus placebo arms. III. To evaluate the application of the Lugano criteria and change in quantitative measurements between pre-AutoHCT and post AutoHCT (e.g. delta standard uptake variable \[SUV\], %SUV decline and %metabolic tumor volume \[MTV\] decline, and other available applicable quantitative measurements) to assess the association between changes in these variables and outcomes, such as PFS and OS. IV. To assess whether the GSTT1 null polymorphism is correlated with pulmonary toxicity after BCNU (carmustine)-containing conditioning regimens as part of autologous stem cell transplantation. V. To assess whether other polymorphisms in the BCNU metabolism pathway or BCNU damage repair pathway(s) are associated with pulmonary toxicity after BCNU-containing conditioning regimens as part of autologous stem cell transplantation. VI. To evaluate whether any of the proposed deoxyribonucleic acid (DNA) polymorphisms are associated with other toxicities. VII. To assess whether DLBCL subtype based on the lymphoma subtyping test (LST) is associated with 24-month PFS, PFS, and OS with ibrutinib compared to placebo in patients treated on this protocol. VIII. To assess whether activating mutations in the BCR pathway are associated with response to ibrutinib and with clinical outcomes in patients treated on this protocol. IX. To assess whether there are any phenotypic associations with IHC markers (particularly MYC protein expression level) and presence of these mutations. X. To assess whether BCL2, MYC, and Ki67 expression by IHC affect clinical outcomes in patients treated on this protocol. XI. To assess whether translocations in MYC with or without BCL2 and BC6 have poor outcomes in patients treated on this protocol and whether ibrutinib modifies the prognosis. OUTLINE: Patients are randomized to 1 of 2 treatment arms. CONDITIONING REGIMEN: ARM I: Investigators may choose to use either the BEAMi (carmustine, etoposide, cytarabine, melphalan, ibrutinib) or CBVi (cyclophosphamide, carmustine, etoposide, ibrutinib) regimen. BEAMi: Patients receive ibrutinib orally (PO) on days -6 to -1, carmustine intravenously (IV) over 2 hours on day -6, etoposide IV twice daily (BID) over 1-2 hours and cytarabine IV BID over 1-2 hours on days -5 to -2, and melphalan IV over 20-30 minutes on day -1. Optionally, if a day of rest is planned, patients may receive BEAMi on days -7 to -2. CBVi: Patients receive ibrutinib PO on days -6 to -1, carmustine IV over 2 hours on day -6, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2. Optionally, if a day of rest is planned, patients may receive CBVi on days -7 to -2. ARM II: Patients receive placebo PO on days -6 to -1 and receive 1 of the 2 conditioning regimens as in Arm I. TRANSPLANT: In both arms, patients undergo autologous hematopoietic progenitor cell or bone marrow transplant on day 0. CONTINUATION REGIMEN: ARM I: Beginning 30-60 days after transplant, patients receive ibrutinib PO on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Beginning 30-60 days after transplant, patients receive placebo PO on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover Arm I. After completion of treatment, patients are followed up every 6 months for up to 60 months from registration.

Interventions

PROCEDUREAutologous Bone Marrow Transplantation

Undergo autologous hematopoietic progenitor cells or bone marrow transplant

PROCEDUREAutologous Hematopoietic Stem Cell Transplantation

Undergo autologous hematopoietic progenitor cells or bone marrow transplant

DRUGCarmustine

Given IV

DRUGCyclophosphamide

Given IV

DRUGCytarabine

Given IV

DRUGEtoposide

Given IV

DRUGIbrutinib

Given PO

OTHERLaboratory Biomarker Analysis

Correlative studies

DRUGMelphalan

Given IV

Correlative studies

OTHERPlacebo Administration

Given PO

Sponsors

National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

* PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0) * Patients must have paraffin tissue from the diagnostic or relapse biopsy available to be submitted for central pathology review; this review is mandatory prior to registration to confirm eligibility and should be initiated as soon as possible * ELIGIBILITY CRITERIA (STEP 1) * Diagnosis of World Health Organization (WHO) diffuse large B-cell lymphoma, non-GCB by central review confirmation * Patient must be deemed eligible to proceed with high-dose chemotherapy and autologous stem cell transplantation by local transplant center * New York Heart Association class I or less; ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or angina pain; patients 60 years or older must have a left ventricular ejection fraction (LVEF) at rest \>= 40% measured by echocardiogram or multi-gated acquisition (MUGA) * Diffusion capacity of the lung for carbon monoxide (DLCO) \>= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards) * Forced expiratory volume in 1 second (FEV1) \>= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards) * Forced vital capacity (FVC) \>= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) unless isolated hyperbilirubinemia attributed to Gilbert's syndrome * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3 x upper limit of normal (ULN) * Creatinine =\< 2.0 mg/dL OR creatinine clearance (calculated clearance permitted) \>= 40 mL/min by Cockcroft-Gault formula * Prothrombin time (PT)/ international normalized ration (INR) \< 1.5 x ULN and partial thromboplastin time (PTT) (activated \[a\]PTT) \< 1.5 x ULN * Patient must have progressed or be refractory to prior anthracycline-containing chemotherapy (e.g. rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone \[R-CHOP\], dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab \[DA-EPOCH-R\], etc) * No more than 3 prior regimens for large cell component (e.g. one induction and two salvage therapies); monoclonal antibody alone or involved field/involved site radiotherapy do not count as lines of therapy. Prior CART therapy is allowed and counts as one line of therapy * Prior use of ibrutinib is allowed unless patient has had disease progression while receiving ibrutinib * Patient must have chemosensitive disease as defined by at least a partial response to salvage therapy at their latest assessment * No major surgery =\< 7 days prior to registration and no minor surgery =\< 3 days prior to registration (with the exception of intravenous access placement, e.g. Hickman or peripherally inserted central catheter \[PICC\]) * Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects; therefore, for women of childbearing potential only, a negative serum pregnancy test must be obtained within 14 days prior to registration * Women of childbearing potential must use adequate contraception from study start to one month after the last dose of protocol therapy; adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence; men must practice complete abstinence or agree to use an adequate contraception method from study start to one month after the last dose of protocol therapy * Age \>= 18 years * Patients should not require chronic use of strong CYP3A inhibitors or strong CYP3A inducers * Patients should not require concurrent therapeutic doses of steroids (\> 20 mg of prednisone/day or equivalent) unless they need them for the indications; steroids should be discontinued for 14 days before starting protocol treatment * Human immunodeficiency virus (HIV) infected patients are eligible provided they meet all other eligibility criteria, and: * There is no prior history of acquired immunodeficiency syndrome (AIDS) defining conditions other than historically low CD4+ T-cell count or B-cell lymphoma * In the opinion of an expert in HIV disease, prospects for long-term survival are excellent were it not for the diagnosis of lymphoma * Use of HIV protease inhibitors as part of the anti-HIV regimen OR as a pharmacologic booster is not allowed * Zidovudine is not allowed * Once daily combination pills for HIV containing a pharmacologic booster such as cobicistat are not allowed * Patients with multi-drug resistant HIV are not eligible * Patients cannot have: * Active central nervous system or meningeal involvement by lymphoma; patients with a history of central nervous system (CNS) or meningeal involvement must be in a documented remission by cerebrospinal fluid (CSF) evaluation and contrast-enhanced magnetic resonance imaging (MRI) imaging for at least 91 days prior to registration * Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy * A known bleeding diathesis * Requirement for warfarin or similar vitamin K antagonists; these drugs are prohibited 28 days prior to the first treatment and throughout the trial * History of stroke or intracranial hemorrhage =\< 6 months before treatment * Currently active, clinically significant hepatic impairment (Child-Pugh class B or C according to the Child Pugh classification * History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study * Serologic status reflecting active hepatitis B or C infection; patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment; (PCR positive patients will be excluded) * Eastern Cooperative Oncology Group (ECOG) performance status must be =\< 2

Design outcomes

Primary

MeasureTime frameDescription
24-month Progression-free Survival (PFS), Defined as the Proportion of Patients Who Are Alive and Progression-free 2 Years From RandomizationTime between registration and disease progression or death, whichever comes first, assessed at 24 monthsWill be assessed using the Lugano classification.

Secondary

MeasureTime frameDescription
Overall Survival (OS)The time between randomization and death from any cause, assessed up to 5 years (60 months)For each arm, the distribution of OS will be estimated using the Kaplan-Meier method. OS will be compared between the two arms using the log-rank test and Cox regression method adjusting for the known predictors.
Time to Hematopoietic EngraftmentFirst day of one week without platelet transfusion, assessed up to 5 yearsWill be defined as platelet count greater than or equal to 20,000/uL following nadir.
PFSTime between registration and disease progression or death, whichever comes first, assessed up to 5 years (60 months)For each arm, the distribution of PFS will be estimated using the Kaplan-Meier method. PFS will be compared between the two arms using the log-rank test and Cox regression method adjusting for the known predictors.
Response Rate Using the Lugano ClassificationUp to 60 monthsThe metabolic response proportion following AutoHCT will be compared between the two arms using chi-squared test.
Treatment-related MortalityUp to 60 monthsTreatment-related mortality will be summarized using contingency tables.
Incidence of Hematologic Toxicity of Ibrutinib TherapyUp to 60 monthsHematologic toxicity will be summarized using contingency tables.
Incidence of Secondary MalignanciesUp to 60 monthsIncidence of secondary malignancies will be summarized using contingency tables.

Countries

Saudi Arabia, United States

Contacts

PRINCIPAL_INVESTIGATORCharalambos B Andreadis

Alliance for Clinical Trials in Oncology

Participant flow

Participants by arm

ArmCount
Arm I (Ibrutinib, Chemotherapy, autoHCT)
CONDITIONING REGIMEN: Investigators may choose to use either the BEAMi or CBVi regimen.\> BEAMi: Patients receive ibrutinib PO on days -6 to -1 or days -7 to -2 if a day of rest is planned, carmustine IV over 2 hours on day -6, etoposide IV BID over 1-2 hours and cytarabine IV BID over 1-2 hours on days -5 to -2, and melphalan IV over 20-30 minutes on day -1. \> CBVi: Patients receive ibrutinib PO on days -6 to -1 or days -7 to -2 if a day of rest is planned, carmustine IV over 2 hours on day -6, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2.\> TRANSPLANT: In both arms, patients undergo autologous hematopoietic progenitor cell or bone marrow transplant on day 0.\> CONTINUATION REGIMEN: Beginning 30-60 days after transplant, patients receive ibrutinib PO on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.\> Autologous Bone Marrow Transplantation: Undergo autologous hematopoietic progenitor cells or bone marrow transplant\> Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous hematopoietic progenitor cells or bone marrow transplant\> Carmustine: Given IV\> Cyclophosphamide: Given IV\> Cytarabine: Given IV\> Etoposide: Given IV\> Ibrutinib: Given PO\> Laboratory Biomarker Analysis: Correlative studies\> Melphalan: Given IV\> Pharmacogenomic Study: Correlative studies
45
Arm II (Placebo, Chemotherapy, autoHCT)
CONDITIONING REGIMEN: Patients receive placebo PO on days -6 to -1 and receive 1 of the 2 conditioning regimens as in Arm I.\> \>\> TRANSPLANT: Patients undergo autologous hematopoietic progenitor cell or bone marrow transplant on day 0.\> \>\> \>\> \>\> \> \>\> \>\> \>\> CONTINUATION REGIMEN: Beginning 30-60 days after transplant, patients receive placebo PO on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover Arm I.\> \>\> \>\> \>\> \> \>\> \>\> \>\> Autologous Bone Marrow Transplantation: Undergo autologous hematopoietic progenitor cells or bone marrow transplant\> \>\> \>\> \>\> \> \>\> \>\> \>\> Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous hematopoietic progenitor cells or bone marrow transplant\> \>\> \>\> \>\> \> \>\> \>\> \>\> Carmustine: Given IV\> \>\> \>\> \>\> \> \>\> \>\> \>\> Cyclophosphamide: Given IV\> \>\> \>\> \>\> \> \>\> \>\> \>\> Cytarabine: Given IV\> \>\> \>\> \>\> \> \>\> \>\> \>\> Etoposide: Given IV\> \>\> \>\> \>\> \> \>\> \>\> \>\> Laboratory Biomarker Analysis: Correlative studies\> \>\> \>\> \>\> \> \>\> \>\> \>\> Melphalan: Given IV\> \>\> \>\> \>\> \> \>\> \>\> \>\> Pharmacogenomic Study: Correlative studies\> \>\> \>\> \>\> \> \>\> \>\> \>\> Placebo Administration: Given PO
43
Safety Cohort
AutoHCT + Ibrutinib (Cycle 1) Ibrutinib 560 mg† days -6 to -1 Ibrutinib Continuation (Cycles 2-13)\*\* Ibrutinib 560 mg daily
6
Total94

Baseline characteristics

CharacteristicArm II (Placebo, Chemotherapy, autoHCT)Arm I (Ibrutinib, Chemotherapy, autoHCT)TotalSafety Cohort
Age, Continuous59 years61 years61 years52.5 years
Baseline Deauville Score
Score 1-2
12 Participants18 Participants30 Participants0 Participants
Baseline Deauville Score
Score 3-4
11 Participants12 Participants23 Participants0 Participants
Baseline Deauville Score
Score 5
5 Participants3 Participants8 Participants0 Participants
ECOG Performance Status
0
18 Participants14 Participants34 Participants2 Participants
ECOG Performance Status
1
23 Participants27 Participants54 Participants4 Participants
ECOG Performance Status
2
2 Participants4 Participants6 Participants0 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
3 Participants2 Participants5 Participants0 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
40 Participants43 Participants89 Participants6 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants
Extranodal Involvement
Bone marrow
3 Participants7 Participants10 Participants0 Participants
Extranodal Involvement
Liver
1 Participants0 Participants1 Participants0 Participants
Extranodal Involvement
Lung
2 Participants6 Participants8 Participants0 Participants
Extranodal Involvement
Other
6 Participants9 Participants17 Participants2 Participants
Extranodal Involvement
Pleura
0 Participants2 Participants2 Participants0 Participants
Extranodal Involvement
Spleen
3 Participants3 Participants8 Participants2 Participants
Extranodal Involvement
Subcutaneous Tissue
1 Participants4 Participants6 Participants1 Participants
LDH229.5 U/L251 U/L235 U/L292.5 U/L
Number of prior lines of chemo2 chemo lines2 chemo lines2 chemo lines2 chemo lines
Prior Ibrutinib0 Participants1 Participants1 Participants0 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
0 Participants1 Participants1 Participants0 Participants
Race (NIH/OMB)
Black or African American
1 Participants3 Participants4 Participants0 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
3 Participants3 Participants9 Participants3 Participants
Race (NIH/OMB)
White
39 Participants38 Participants80 Participants3 Participants
Refractory Disease8 Participants10 Participants20 Participants2 Participants
Sex: Female, Male
Female
20 Participants20 Participants41 Participants1 Participants
Sex: Female, Male
Male
23 Participants25 Participants53 Participants5 Participants
Stage of Disease at Relapse
I
4 Participants3 Participants7 Participants0 Participants
Stage of Disease at Relapse
II
7 Participants11 Participants19 Participants1 Participants
Stage of Disease at Relapse
III
11 Participants11 Participants24 Participants2 Participants
Stage of Disease at Relapse
IV
21 Participants20 Participants44 Participants3 Participants
Time to relapse
> 12 months
22 Participants24 Participants47 Participants1 Participants
Time to relapse
<= 12 months (includes refractory)
21 Participants21 Participants47 Participants5 Participants
Type of transplant regimen planned
BEAM
41 Participants42 Participants88 Participants5 Participants
Type of transplant regimen planned
CBV
2 Participants3 Participants6 Participants1 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
deaths
Total, all-cause mortality
14 / 4510 / 433 / 62 / 2
other
Total, other adverse events
36 / 4538 / 436 / 61 / 2
serious
Total, serious adverse events
22 / 4523 / 434 / 61 / 2

Outcome results

Primary

24-month Progression-free Survival (PFS), Defined as the Proportion of Patients Who Are Alive and Progression-free 2 Years From Randomization

Will be assessed using the Lugano classification.

Time frame: Time between registration and disease progression or death, whichever comes first, assessed at 24 months

Population: Participants that completed at least one cycle of treatment

ArmMeasureValue (NUMBER)
Arm I (Ibrutinib, Chemotherapy, autoHCT)24-month Progression-free Survival (PFS), Defined as the Proportion of Patients Who Are Alive and Progression-free 2 Years From Randomization0.576 proportion of participants
Arm II (Placebo, Chemotherapy, autoHCT)24-month Progression-free Survival (PFS), Defined as the Proportion of Patients Who Are Alive and Progression-free 2 Years From Randomization0.408 proportion of participants
Secondary

Incidence of Hematologic Toxicity of Ibrutinib Therapy

Hematologic toxicity will be summarized using contingency tables.

Time frame: Up to 60 months

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
Arm I (Ibrutinib, Chemotherapy, autoHCT)Incidence of Hematologic Toxicity of Ibrutinib TherapyGrade 3 Event6 Participants
Arm I (Ibrutinib, Chemotherapy, autoHCT)Incidence of Hematologic Toxicity of Ibrutinib TherapyGrade 4 Event13 Participants
Arm I (Ibrutinib, Chemotherapy, autoHCT)Incidence of Hematologic Toxicity of Ibrutinib TherapyGrade 5 Event0 Participants
Arm II (Placebo, Chemotherapy, autoHCT)Incidence of Hematologic Toxicity of Ibrutinib TherapyGrade 5 Event0 Participants
Arm II (Placebo, Chemotherapy, autoHCT)Incidence of Hematologic Toxicity of Ibrutinib TherapyGrade 3 Event9 Participants
Arm II (Placebo, Chemotherapy, autoHCT)Incidence of Hematologic Toxicity of Ibrutinib TherapyGrade 4 Event11 Participants
Secondary

Incidence of Secondary Malignancies

Incidence of secondary malignancies will be summarized using contingency tables.

Time frame: Up to 60 months

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm I (Ibrutinib, Chemotherapy, autoHCT)Incidence of Secondary Malignancies1 Participants
Arm II (Placebo, Chemotherapy, autoHCT)Incidence of Secondary Malignancies0 Participants
Secondary

Overall Survival (OS)

For each arm, the distribution of OS will be estimated using the Kaplan-Meier method. OS will be compared between the two arms using the log-rank test and Cox regression method adjusting for the known predictors.

Time frame: The time between randomization and death from any cause, assessed up to 5 years (60 months)

Secondary

PFS

For each arm, the distribution of PFS will be estimated using the Kaplan-Meier method. PFS will be compared between the two arms using the log-rank test and Cox regression method adjusting for the known predictors.

Time frame: Time between registration and disease progression or death, whichever comes first, assessed up to 5 years (60 months)

Secondary

Response Rate Using the Lugano Classification

The metabolic response proportion following AutoHCT will be compared between the two arms using chi-squared test.

Time frame: Up to 60 months

ArmMeasureValue (NUMBER)
Arm I (Ibrutinib, Chemotherapy, autoHCT)Response Rate Using the Lugano Classification0.590 proportion of participants
Arm II (Placebo, Chemotherapy, autoHCT)Response Rate Using the Lugano Classification0.553 proportion of participants
Secondary

Time to Hematopoietic Engraftment

Will be defined as platelet count greater than or equal to 20,000/uL following nadir.

Time frame: First day of one week without platelet transfusion, assessed up to 5 years

ArmMeasureValue (MEDIAN)
Arm I (Ibrutinib, Chemotherapy, autoHCT)Time to Hematopoietic Engraftment14.0 days
Arm II (Placebo, Chemotherapy, autoHCT)Time to Hematopoietic Engraftment14.5 days
Secondary

Treatment-related Mortality

Treatment-related mortality will be summarized using contingency tables.

Time frame: Up to 60 months

ArmMeasureGroupValue (NUMBER)
Arm I (Ibrutinib, Chemotherapy, autoHCT)Treatment-related MortalityDisease-related6 participants
Arm I (Ibrutinib, Chemotherapy, autoHCT)Treatment-related MortalityInfection4 participants
Arm I (Ibrutinib, Chemotherapy, autoHCT)Treatment-related MortalityNew Primary1 participants
Arm I (Ibrutinib, Chemotherapy, autoHCT)Treatment-related MortalityOther/Unknown2 participants
Arm II (Placebo, Chemotherapy, autoHCT)Treatment-related MortalityOther/Unknown4 participants
Arm II (Placebo, Chemotherapy, autoHCT)Treatment-related MortalityDisease-related8 participants
Arm II (Placebo, Chemotherapy, autoHCT)Treatment-related MortalityNew Primary0 participants
Arm II (Placebo, Chemotherapy, autoHCT)Treatment-related MortalityInfection0 participants
Other Pre-specified

BCL2, MYC, and Ki67 Expression in Tissue Samples by Immunohistochemistry (IHC)

The expression of BCL2, MYC, and Ki67 will be analyzed to assess whether they affect clinical outcomes.

Time frame: Baseline

Other Pre-specified

BCR Pathway Mutations

The mutation of CD79a/b, caspase recruitment domain family, member 11 (CARD11), tumor necrosis factor, alpha-induced protein 3 TNFAIP3), and myeloid differentiation primary response 88 (MYD88) will be associated with each outcome in the ibrutinib arm (Arm A) using the chi-squared test for response rate and the log-rank test for each censored outcome. Similar analyses will be conducted for the placebo arm (Arm B) to show that the association between mutation and the outcomes observed in the ibrutinib arm is not observed in the placebo arm.

Time frame: Baseline

Other Pre-specified

Fludeoxyglucose Positron Emission Tomography (FDG-PET) Imaging Results

PFS and OS will be compared between PET/computed tomography (CT) positive and negative groups using the two-sample log-rank test with a 2-sided alpha of 5%. A Cox regression model will be conducted to regress PFS and OS on PET/CT positivity. Deauville criteria analyses will be conducted with cutoffs at scores of 2 and 3, and quantitative measurements, e.g. delta standard uptake value (SUV), %SUV decline and %MTV decline, in place of the dichotomous FDG-PET/CT outcome. Positive/negative predictive values, sensitivity and specificity of PET/CT further estimated by dichotomizing the PFS and OS at 2 years.

Time frame: Baseline

Other Pre-specified

GSTT1 Null Allele Expression

GSTT1 null allele expression will be associated with carmustine toxicity. Quantified using the standard Common Terminology Criteria for Adverse Events and changes in diffusing capacity of the lungs for carbon monoxide from baseline.

Time frame: Baseline

Other Pre-specified

MYC Translocations

Translocations in MYC with or without BCL2, and BCL6 will be analyzed to determine whether they are related to poor outcomes and whether ibrutinib modifies the prognosis.

Time frame: Baseline

Other Pre-specified

Single-nuclear Polymorphisms (SNPs) in the BCNU Metabolism or Damage Repair Pathways

All SNPs will be evaluated for deviation from Hardy-Weinberg. In the absence of a hypothesized effect, analyses will be powered for allele dosing (i.e., additive) effects. The Cochran-Armitage test (for binary endpoints), Jonkheere-Terpstra test (for quantitative traits including biomarker or gene expressions in serum or tumor ribonucleic acid) and the Cox score test (for censored time-to-event outcomes) will be used to quantify marginal associations. Multivariable models, with molecular, clinical and demographic variables, will be constructed using conditional inference trees and random forests.

Time frame: Baseline

Source: ClinicalTrials.gov · Data processed: Apr 4, 2026